Progress in the research funded by this grant has led to the discovery that the Osteopontin gene specifies two distinct isoforms through differential translation of a single Opn RNA species: a cytokine in T cells and a critical intracellular protein expressed in dendritic cells. We have shown that Opn expression in plasmacytoid dendritic cells is essential for production of this cell's signature cytokine- interferon alpha. We have recently discovered that robust Th17 responses depend on the ability of a newly-defined intracellular Opn isoform- Opn-i - to inhibit secretion of IL-27 by DC. We have also defined an Opn-i-dependent interaction that prevents efficient development of Th17 responses. Interferon alpha/beta receptor (IFNAR)-dependent inhibition of Opn-i expression releases the brakes on IL-27 secretion and inhibits the Th17 response to self-peptides. Definition of the impact of this IFNAR:Opn-i axis on the Th1 and Th17 response has provided new insight into the basis for the therapeutic effects of IFN-I in Multiple Sclerosis and other Th17 diseases, as well as a rationale for new therapeutic approaches that engage this IFNAR:Opn-i pathway. We propose experiments (1) to define the genetic mechanism resulting in generation of Opn-i and Opn-s expression in DC and T cells;(2) to define the interaction between Opn-i and the MyD88 signaling module in plasmacytoid DC leading to IFN1 expression and enhanced Th1 development;(3) to analyze Opn-dependent interactions in conventional DC that regulate antigen presentation and Th17 development and (4) to generate mice that selectively express distinct Opn isoforms so that we may determine the contribution of Opn isoforms to the immune response to foreign and self antigens in the context of Experimental Autoimmune Encephalomyelitis (EAE mu model of MS.
The Osteopontin (Opn) gene is important in diverse biological processes, including immune responses, vascularization and bone formation, through its interaction with different cell types. Our recent discovery of the contribution of distinct secreted and intracellular isoforms of Opn to the generation of Th17 and Th1 subsets fills an important gap in understanding the genesis of these subsets in normal and autoimmune responses. We will generate mutant mice that express the intracellular or secreted Opn isoform for analysis of the contribution of each to protection again infection and in a murine model of Multiple Sclerosis.
|Leavenworth, Jianmei W; Verbinnen, Bert; Yin, Jie et al. (2015) A p85Î±-osteopontin axis couples the receptor ICOS to sustained Bcl-6 expression by follicular helper and regulatory T cells. Nat Immunol 16:96-106|
|Yin, Jie; Leavenworth, Jianmei W; Li, Yang et al. (2015) Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci U S A 112:15988-93|
|Leavenworth, Jianmei W; Verbinnen, Bert; Wang, Qin et al. (2015) Intracellular osteopontin regulates homeostasis and function of natural killer cells. Proc Natl Acad Sci U S A 112:494-9|
|Kim, Hye-Jung; Cantor, Harvey (2014) CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res 2:91-8|
|Cantor, Harvey; Shinohara, Mari L (2009) Regulation of T-helper-cell lineage development by osteopontin: the inside story. Nat Rev Immunol 9:137-41|
|Shinohara, Mari L; Kim, June-Ho; Garcia, Virgilio A et al. (2008) Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity 29:68-78|
|Shinohara, Mari L; Kim, Hye-Jung; Kim, June-Ho et al. (2008) Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells. Proc Natl Acad Sci U S A 105:7235-9|
|Lu, Linrong; Werneck, Miriam B F; Cantor, Harvey (2006) The immunoregulatory effects of Qa-1. Immunol Rev 212:51-9|
|Shinohara, Mari L; Lu, Linrong; Bu, Jing et al. (2006) Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol 7:498-506|
|Shinohara, Mari L; Jansson, Marianne; Hwang, Eun Sook et al. (2005) T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc Natl Acad Sci U S A 102:17101-6|
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